Understanding Heterogeneity and Permeability of Brain Metastases in Murine Models of HER2-Positive Breast Cancer Through Magnetic Resonance Imaging: Implications for Detection and Therapy

Abstract

OBJECTIVES: Brain metastases due to breast cancer are increasing, and the prognosis is poor. Lack of effective therapy is attributed to heterogeneity of breast cancers and their resulting metastases, as well as impermeability of the blood–brain barrier (BBB), which hinders delivery of therapeutics to the brain. This work investigates three experimental models of HER2 + breast cancer brain metastasis to better understand the inherent heterogeneity of the disease. We use magnetic resonance imaging (MRI) to quantify brain metastatic growth and explore its relationship with BBB permeability. DESIGN: Brain metastases due to breast cancer cells (SUM190-BR3, JIMT-1-BR3, or MDA-MB-231-BR-HER2) were imaged at 3 T using balanced steady-state free precession and contrast-enhanced T1-weighted spin echo sequences. The histology and immunohistochemistry corresponding to MRI were also analyzed. RESULTS: There were differences in metastatic tumor appearance by MRI, histology, and immunohistochemistry (Ki67, CD31, CD105) across the three models. The mean volume of an MDA-MB-231-BR-HER2 tumor was significantly larger compared to other models (F2,12 = 5.845, P < .05); interestingly, this model also had a significantly higher proportion of Gd-impermeable tumors (F2,12 = 22.18, P < .0001). Ki67 staining indicated that Gd-impermeable tumors had significantly more proliferative nuclei compared to Gd-permeable tumors (t[24] = 2.389, P < .05) in the MDA-MB-231-BR-HER2 model. CD31 and CD105 staining suggested no difference in new vasculature patterns between permeable and impermeable tumors in any model. CONCLUSION: Significant heterogeneity is present in these models of brain metastases from HER2 + breast cancer. Understanding this heterogeneity, especially as it relates to BBB permeability, is important for improvement in brain metastasis detection and treatment delivery.

Characterization of passive permeability at the blood–tumor barrier in five preclinical models of brain metastases of breast cancer

“…Consistent with previous work [31,46], we demonstrate that changes in passive permeability are independent of lesion size, and do not appear to be related to tumor morphology. Moreover, the observed BTB permeability at different locations within the brain did not appear to influence permeability in these models supporting previous MRI studies examining the distribution of gadolinium-enhancing metastases in similar preclinical models [19].…”

“…The brain distribution of metastatic foci in each model presented herein appear consistent with similar studies demonstrating more than 50% of metastatic burden occurs in cortical regions, with relatively fewer lesions occurring in the central brain regions, and the least metastatic growth observed in the posterior and olfactory regions [47,48]. Additionally, this work agrees with previous findings [46] suggesting the presence of HER2 does not seem to correlate strongly with changes in vascular permeability (permeability of JIMT-1-BR3, SUM190-BR3, and MDA-MB-231BR-HER2+ lines were not congruent) and that permeability changes appear to be more cell line specific (i.e., MDA-BB-231BR and MDA-MB-231BR-HER2+). Interestingly, Murell et.…”

Brain Distribution of a Novel MEK Inhibitor E6201: Implications in the Treatment of Melanoma Brain Metastases

“…Focal therapies with surgical resection and/or radiosurgery can effectively control an individual metastasis, but the risk of developing subsequent brain metastases elsewhere in the brain exceeds 50%, which suggests that integrating these procedures with effective targeted therapies may provide significant clinical benefit (Fife et al, 2004). The successful treatment of brain tumors will need targeted therapies that are: 1) potent against its target, 2) capable of penetrating an intact blood-brain barrier (BBB) replete with efflux transporters (Osswald et al, 2016), and 3) capable of reaching the protected tumor cells that are not clinically detectable upon contrast-enhancing magnetic resonance imaging (Murrell et al, 2015). Many small-molecule molecularly-targeted therapies have limited ability to permeate an intact BBB, which in turn can limit their efficacy against brain tumors (Agarwal et al, 2011;Gampa et al, 2016Gampa et al, , 2017.…”

Foe or friend? Janus-faces of the neurovascular unit in the formation of brain metastases

“…208 Recent data suggest that gadolinium-DTPAimpermeable cerebral breast metastases have significantly more proliferative nuclei compared to gadolinium-DTPA-permeable tumors in the mouse brain. 209 In contrast, another study showed that melanoma metastases having a permeable vasculature grow faster than those having an intact BTB. 144 This study also demonstrated that only brain-permeable PI3K inhibitors are active against metastatic lesions, and that targeting micrometastases and even dormant cells is more effective than treating large lesions.…”